Treatment of HIV-infected individuals is one of the most pressing biomedical problems of recent times. A promising new therapy has emerged as an important method for preventing or inhibiting the rapid proliferation of the virus in human tissue. HIV-protease inhibitors block a key enzymatic pathway in the virus resulting in substantially decreased viral loads, which slows the steady decay of the immune system and its resulting deleterious effects on human health. The HIV-protease inhibitor nelfinavir mesylate of formula 7
has been shown to be an effective treatment for HIV-infected individuals. Nelfinavir mesylate is disclosed in U.S. Pat. No. 5,484,926, issued Jan. 16, 1996. This patent is entirely incorporated by reference into this patent application.
The present inventors have discovered useful intermediate compounds that can be used in several reaction schemes to make nelfinavir mesylate. The present inventors also have discovered new methods for making nelfinavir mesylate from the free base nelfinavir of formula 4: 
The nelfinavir free base also is disclosed in U.S. Pat. No. 5,484,926.
It is an object of this invention to provide compounds and intermediates useful for making HIV-protease inhibitors and methods of making HIV-protease inhibitors. Such inhibitors are useful for treating HIV-infected individuals.
In a first aspect, the invention relates to compounds of formula 3: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10 
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with the proviso that when R1 is xe2x80x94CH3, X cannot be xe2x80x94OCH3 or xe2x80x94OH, and when R1 is CH3C(O)xe2x80x94, X cannot be xe2x80x94OH;
or a pharmaceutically acceptable salt or solvate thereof.
In various preferred embodiments of the invention, R1 is xe2x80x94C(O)CH3 and/or X is a halogen, preferably, Cl.
In another aspect, the invention relates to compounds of formula 2: 
wherein R1 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula 8
wherein R2 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or a pharmaceutically acceptable salt or solvate thereof.
This invention further relates to methods for making the compounds of formulae 2 and 3. In a method for making a compound of formula 2: 
a compound according to formula 1, shown below, 
is reacted under suitable and sufficient conditions to add an R1 protecting group and form a compound of formula 2. In this instance, R1 is a C2 to C8 alkyl group; a cycloalkyl group; a heterocycloalkyl group; an aryl group; a heteroaryl group; or a group of formula 8
wherein R2 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or R1 is a group of formula 9
wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.
This invention includes a method of making a compound according to formula 3
This method includes adding, under suitable and sufficient conditions, a suitable protecting group R1 and a leaving group X to a compound of formula 1
In this instance, R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or R1 is a group of formula 9
wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with the proviso that when R1 is xe2x80x94CH3, X cannot be xe2x80x94OCH3 or xe2x80x94OH, and when R1 is CH3C(O)xe2x80x94, X cannot be xe2x80x94OH. As noted above, in certain embodiments, R1 is xe2x80x94C(O)CH3 and/or X is a halogen, preferably, Cl.
A compound according to formula 3, as defined above, also can be made from a compound of formula 2. The reaction proceeds by adding a suitable leaving group X to the compound of formula 2. In this instance, formula 2 is as defined below: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group. Additionally, in this instance, X is defined as OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen. In this method, when R1 is xe2x80x94CH3, X cannot be xe2x80x94OCH3 or xe2x80x94OH, and when R1 is CH3C(O)xe2x80x94, X cannot be xe2x80x94OH.
This invention further relates to methods for making HIV-protease inhibitors. One HIV-protease inhibitor produced by a method according to this invention is a compound of formula 4, illustrated below: 
In this method, a compound of formula 3
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen,
is reacted under suitable and sufficient conditions to form the compound of formula 4. Again, for one preferred embodiment of this process, the variable R1 represents xe2x80x94C(O)CH3 and/or the variable X represents Cl.
The compound according to formula 4, identified above, also can be prepared by deprotecting a compound of formula 5
and reacting with it, under sufficient conditions, a compound of formula 3. In this instance, the compound according to formula 3 is 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen.
In another embodiment of this invention, a compound of formula 4, as identified above, can be prepared by combining a compound of formula 3: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen,
with a compound of formula 6
under conditions sufficient and suitable to obtain the compound of formula 4.
This invention further relates to methods of making a compound of formula 7. In one embodiment, the compound of formula 7
is produced by converting a compound of formula 4
under sufficient and suitable conditions to the compound of formula 7. In this method, the conversion of the compound of formula 4 to the compound of formula 7 takes place by:
(a) contacting the compound of formula 4 with an organic solvent;
(b) contacting the compound of formula 4 with methanesulfonic acid under conditions sufficient to form a compound of formula 7; and
(c) spray drying the compound of formula 7. In a more specific embodiment of this method, the organic solvent is ethanol.
In another method for making a compound of formula 7 from a compound of formula 4, the following procedure is followed:
(a) the compound of formula 4, a suitable solvent, and methanesulfonic acid are combined to form the compound of formula 7, the compound of formula 7 being dissolved in solution;
(b) a first antisolvent is added to the solution containing the compound of formula 7;
(c) the compound of formula 7 and the first antisolvent are agitated together to form a product having a solid phase and a liquid phase; and
(d) the product is filtered and washed with a second antisolvent, the second antisolvent being the same as or different from the first antisolvent, to obtain a solid final product according to formula 7. After the solid final product is washed, it can be dried by any appropriate method or means. Tetrahydrofuran can be used as the solvent, and diethylether can be used as at least one antisolvent, preferably at least the first antisolvent.
This invention also relates to a method of making a compound according to formula 4 (as defined above) from a compound according to formula 2. In this method, a compound according to formula 2 is reacted under sufficient and suitable conditions to form the compound of formula 4. In this instance, the compound of formula 2 is defined as follows: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R1 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.
Yet another embodiment of this invention relates to a method of making a compound of formula 7, defined above. In this method, a compound according to formula 5
is deprotected. Then, the deprotected compound of formula 5 is reacted, under sufficient and suitable conditions, with a compound of formula 3. Formula 3, in this instance, is defined as follows: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen. The reaction of compounds 3 and 5 produces a compound of formula 4, described above. The compound according to formula 4 is then converted to the compound of formula 7, for example, by one of the methods described above.